Age-associated inflammation impairs myeloid development and monocyte and macrophage function

Abstract

As the population ages, the burden of chronic inflammatory disease increases and novel interventions to keep older adults healthier for longer are urgently required. Individuals with lower than age-average levels of circulating inflammatory cytokines (e.g. TNF, IL-6) appear to live longer, healthier lives. Our data suggest that chronic exposure to inflammation in the aging microenvironment alters myeloid cell production and function, which ultimately impacts health. In humans (20-100yo) we found that serum cytokines and health conditions were stronger predictors of myeloid cell numbers, and monocyte maturity and activation than age alone. Individuals with more chronic conditions had more myeloid derived suppressor cells and a higher ratio of CD16+ to CD14+ monocytes. Markers of monocyte activation (e.g. CCR2, CX3CR1, HLA-DR, CD16) were elevated in chronic inflammatory states (e.g. rheumatoid arthritis, RA; osteoarthritis, OA) when compared to healthy age- and sex-matched controls. CCR2 expression on monocytes correlated with pain in RA and OA. Following DMARD treatment in RA patients, inflammation, monocyte CCR2 expression, and disease activity decreased. Myeloid cells expand with age in both mice and humans. In mice, we found that this resulted from increased monopoiesis in the bone marrow and the spleen. Using heterochronic bone marrow chimeras, we determined that this process is driven by tumour necrosis factor (TNF) from the aging microenvironment. Transcriptomic analysis of both circulating monocytes and alveolar macrophages revealed decreased expression of genes involved in myeloid lineage commitment and iv maturation (i.e. HDAC1, TET2, FOXO3) in old WT mice, but not in in old TNF KOs. Although myeloid cells increase with age, their function is impaired. We found that both life-long and acute exposure to TNF can impair phagolysosomal fusion and decrease bacterial killing capacity of macrophages. Overall, these studies demonstrate that age-associated inflammation accelerates myeloid cell production at the expense of proper differentiation and function.